Mononuclear phagocytes (monocytes and macrophages) play a major role in the body as participants in inflammatory, clotting, and immune reactions, and as effectors in the mediation of tissue damage and degradation, and cell mediated resistance to microbes and neoplastic cells. Mononuclear phagocytes produce several factors that control the differentiation and function of other cells. In the chronic synovitis of rheumatoid arthritis control the inflammation. This proposal will focus on mononuclear phagocytes in rheumatoid arthritis by investigating in detail the importance of tumor necrosis factor-cachectin (TNF) and gamma interferon (IFN-gamma) and interleukin-1 (IL-1), fibrin and plasmin, and alpha 2 macroglobulin (alpha 2M) in the generation, maintenance, and control of rheumatoid arthritis-synovitis. The specific aims of this proposal are: to investigate the influences of TNF, IL-1, IFN-gamma in different macrophages, and cells from the synovium (the type A macrophage-like cells and the type B fibroblast-like cells); to investigate the role of clotting in fibrinolysis in rheumatoid synovitis; to investigate the role of alpha2M in the regulation of inflammatory and immune responses in rheumatoid synovitis. The results of the planned experiments will be especially significant in adding to our knowledge of rheumatoid arthritis and may lead to the development of better ways of preventing and/or treating this disease.